For individuals who are infected with hepatitis C virus (HCV), knowledge of co-factors affecting the occurrence of liver disease is crucial. However, the mechanisms of HCV-associated pathogenesis, particularly with regard to the role of the virus and the host immune response, remain unclear. The primary goal of the proposal is to elucidate the natural history of HCV infection with respect to progression to hepatocellular carcinoma (HCC) and other health outcomes in a Japanese community-based population in which infection with HCV is highly endemic. As part of an annual ultrasonographic tomography screening program in this population, nearly 1,000 adult residents with HCV have been under surveillance for liver cancer since 1994. The proposed study will extend the observation of this cohort, with the additional collection and analysis of virologic, epidemiologic, and clinical data. The specific aims of the research are: to determine the predictive value of markers of HCV infection in the development of liver damage and HCC; to estimate the effect of host-related factors, including heavy alcohol consumption, cigarette smoking, and diet, on HCV-induced liver disease progression and hepatocarcinogenesis; to examine the role of co-infection with hepatitis B virus and human T-lymphotropic virus type I in the natural history of HCV; to characterize the function of host immune status and response in the persistence of HCV infection as well as in the progression of liver disease and HCC among HCV carriers; to evaluate the utility of serologic markers of liver damage in predicting the development of HCC in individuals infected with HCV; to identify predictors of extrahepatic morbidity and mortality among HCV carriers. The uniqueness of the study population and the richness of the data parameters combined with the extensive experience of the assembled multi-disciplinary team provide an important opportunity to increase our understanding of the natural history of HCV and to contribute to our ability to identify and potentially treat those carriers who are at increased risk of an adverse outcome related to their HCV infection.